Type II diabetes is chronic disease characterized by temporal loss of ?-cell function and gradual insulin deficiency. Despite years of intensive research into the mechanisms of ?-cell functional decline, progress in understanding the pathogenesis of diabetes has been hampered by our inability to monitor the fate of ?-cells during progression of the disease or during therapeutic recovery. Although various molecular imaging approaches have been demonstrated in vitro, non-invasive imaging of ?-cell mass and function in vivo remains elusive. Over the past 5 years, our lab has improved upon the original design of a responsive MRI contrast agent that responds to release of Zn2+ ions from secretory tissues and demonstrated that release of insulin and Zn2+ from pancreatic ?-cells initiated by a bolus of glucose bolus can be imaged in rodents and in the macaque non-human primate. The monkey imaging studies showed that Zn2+ and insulin secretion is not uniform throughout the pancreas, consistent with known data on the non-uniform distribution of islets throughout the pancreas. A reduction in agent Zn2+ binding affinity (by ~103) resulted in a dramatic improvement in the sensitivity for detection of Zn2+ secretion from the pancreas in vivo. Furthermore, we have demonstrated that one can detect ?first responder islets? as ?hot spots? in the tail of the pancreas by MRI using either a low or high affinity Zn2+ sensor. In this continuation project, we will monitor first responder islets in two well-established T2DM model, the Zucker Diabetic Fatty (ZDF) rat (obese model) and the Goto-Kakizaki (GK) rat (non-obese model). Animals will be imaged every 2 weeks during progression of the disease and as they respond to clinically approved T2DM drugs. The imaging methods will be validated by independent measures of insulin content (fluorescence) and Zn2+ content by SR-XRF. Our goal is to demonstrate that ?-cell function can be monitored in the head and tail regions of the pancrease reproducibly by MRI and that this technology will provide new insights into ?-cell function that will catalyze development of new drugs for T2DM.